Tetrahydropyridine derivatives

ABSTRACT

Tetrahydropyridine derivatives and processes for the preparation thereof are disclosed. These tetrahydropyridine compounds are useful as psychosedative agents.

O Unlted States Patent 1191 1111 3,

Edenhofer Dec. 16, 1975 TETRAHYDROPYRIDINE DERIVATIVES [51] Int. Cl. C07D 213/69 Inventor: Albrecht Edenhofer, Riehen Fleld Of Search G Switzerland [73] Assignee: Hoffmann-La Roche Inc., Nutley, [56] References cued N J UNITED STATES PATENTS 3,674,799 7/1972 Edenhofer et al. 260/294.8 G [22] Ffled' 1975 3,706,755 12/1972 Edenhofer et al. 260/297 R [21] Appl. No.: 540,755

Primary ExaminerAlan L. Rotman [62] z i g gg j fi 2?: P t N Attorney, Agent, or FirmSamuel L. Welt; Bernard S.

lVlSlOl'l O 61'. O. ay a O. 3,879,405, which is a division of Ser. No. 148,119, Leon Frank Hoffman May 28, 1971, Pat. No. 3,758,483. [57] ABSTRACT [30] Forelgn Apphcat'on Pmmty Data Tetrahydropyridine derivatives and processes for the June 19, 1970 Switzerland, 9318/70 preparation thereof are disclosed. These tetrahydropyridine compounds are useful as psychosedative [52] US. Cl ..260/294.8 G; 260/294.8 F;- agents. I

260/29'5 AM; 260/296 R; 260/297 R; 424/263 1 Claim, No Drawings Rl-N DESCRIPTION OF THE INVENTION The present invention relates to novel chemical compounds and to processes for the preparation thereof, said compounds having valuable therapeutic properties. More particularly, the present invention is concerned with new tetrahydropyridine derivatives of the general formula wherein R signifies hydrogen, lower alkyl, lower alkanoyl, lower alkyl-sulfonyl, cycloalkyl or cycloalkyllower alkyl; R signifies hydrogen, lower alkyl, cycloalkyl or cycloalkyl-lower alkyl; R signifiesfluorine, chlorine or lower alkoxy; X signifies an oxygen atom or a sulfur atom and the pharrnaceutically acceptable acid addition salts thereof.

As used herein, either alone or in combination such as in lower alkyl-sulfonyl, the term lower alkyl comprehends straight or branched chain hydrocarbon groups having from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-hexyl and the like. The term lower alkoxy designates straight or branched chain saturated hydrocarbonoxy groups containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy and the like. The term lower alkanoyl denotes the residue of a straight or branched chain aliphatic carboxylic acid, containing from 1 to 7 carbon atoms, for example formyl, acetyl, propionyl, isobutyryl and n-valeryl. The term cycloalkyl encompasses cyclic hydrocarbon groups having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and the like. Examples of the cycloalkyl-lower alkyl groups include cyclopropyl-methyl, cyclopropyl-ethyl and the like.

A preferred class of compounds falling within the scope of formula I are those wherein X represents an oxygen atom, i.e., compounds of the formula Rlf-N wherein R R are as described above.

Another preferred class of compounds falling within the scope of formula I are those wherein R signifies fluorine, i.e., compounds of the formula wherein R R and X are as described above.

Particularly preferred of the compounds of formula I above are those wherein R represents a lower alkanoyl group, preferably the acetyl group, R represents hydrogen, R represents fluorine and X represents oxygen. Most preferred of the compounds of formula I is:

The novel compounds of formula I can be prepared following a variety of synthetic routes.

A. In one such process aspect, the compounds of formula I above can be prepared by condensing a compound of the general formula x-cn -crr -z R N wherein R,, R and X are as described above and Z represents a suitable leaving group with a compound of the general formula III The condensation of a compound of formula II with a compound of formula III is expediently effected in the presence of a polar organic solvent. Suitable for this purpose are lower alkanols such as methanol, ethanol, isopropanol and the like; cyclic ethers such as tetrahydropyran and dioxane; and dimethylformamide or dimethyl sulfoxide. The condensation is advantageously effected at a temperature between room temperature and the reflux temperature of the reaction mixture. Where, in the starting material of formula II the leaving group designated as Z represents a halogen atom or a lower alkyl or aryl-sulfonyloxy group, the condensation reaction is preferably carried out in the presence of an acid binding agent, for example in the presence of an alkali carbonate such as potassium carbonate.

The starting materials of formula II above may be prepared by reacting a compound of the formula XII IV R wherein R R and X are as described above with a 2-halo-ethanol of the formula haloCH CH OH v to yield a compound of the formula X-- CHaCHQOH VI wherein R R and X are as described above.

The compound of formula VI so obtained can then be reacted with a halogenating agent, such as thionyl chloride to obtain the compound of formula II wherein Z signifies halogen. This halogenation reaction is preferably effected in the presence of an inert organic solvent such as chloroform or benzene at a temperature between about room temperature and the reflux temperature of the reaction mixture.

Alternately, the compound of formula VI above can be reacted with an alkylor arylsubstituted sulfonic acid halide, preferably the chloride, to yield the desired compound of formula II wherein Z signifies an alkylor arylsulfonyloxy group. This reaction is expediently effected in the presence of an acid binding agent at a temperature between about C and room temperature.

The compounds of formula II above wherein Z represents the group N(R,) A R and A being as defined above, can be prepared by amination of the corresponding compounds of formula II wherein Z signifies halogen. This amination can be effected by reacting the halo-substituted compound of formula II with a dialkylamine, preferably dimethylamine; this reaction is expediently effected in a closed vessel at an elevated temperature, for example between about 50 and 150C. The product obtained as a result of this amination is subsequently quaternized by reaction with an alkylating agent such as an alkyl chloride, alkyl bromide or alkyl sulfate, preferably methyl chloride, methyl bromide or dimethyl sulfate. The quaternization is preferably carried out at a temperature of from about room temperature to about C. Both the amination and quaternization are expediently carried out in the presence of an inert solvent such as an alkanol, i.e., methanol, or in dioxane or benzene.

The starting materials of formula II wherein X signifies oxygen and the leaving group Z is a halogen atom may also be prepared by reacting a compound of formula IV wherein X is oxygen with an excess of a 1,2- dihaloethane, preferably 1,2-dibromoethane in the presence of an excess of aqueous alkali, preferably caustic soda. This reaction is preferably carried out at a temperature between room temperature and the boiling point of the reaction mixture.

The starting materials of formula III wherein R signifies lower alkoxy can be prepared, for example, by employing a Grignard reaction. Thus, for instance, the reaction between N-benzyl-4-piperidone and pmethoxy-phenyl magnesium bromide, followed by hydrogenolytic cleavage of the benzyl group and treatment with a dehydrating agent such as, for example, thionyl chloride or alcoholic hydrochloric acid, yields the desired compound of formula III wherein R is methoxy.

B. In another process aspect of the present invention, the compounds of formula I above can be prepared by reacting a compound of the formula Rr-N VII

wherein R R and X are as described above and M signifies an alkali metal or a halomagnesium radical with a compound of the formula L- CHz-CHz M VIII wherein R is as described above and L is a suitable leaving group.

The substituent M in the starting materials of formula VII preferably represents an alkali metal, especially sodium or potassium. In addition, M can also represent a halo-magnesium radical such as the bromo-magnesium or chloro-magnesium radical.

The leaving group in the compounds of formula VIII designated by the symbol L is preferably a halogen atom, especially chlorine or bromine, or an alkylor aryl-sulfonyloxy group, especially mesyloxy or tosyloxy.

The reaction between a compound of formula VII wherein M is potassium an alkali metal and a compound of formula VIII is effected in the presence of an alkali alkanolate, for example sodium ethanolate, in the corresponding alkanol, for example, ethanol. When the M substituent in the compounds of formula VII represents a halo-magnesium radical, the reaction of this formula VII compound with a compound of formula VIII is preferably carried out in a polar organic solvent such as in an ether, i.e., dimethyl ether, tetrahydrofuran or dioxane. This reaction is preferably carried out at a temperature between room temperature and the reflux temperature of the reaction mixture.

The starting materials of formula VIII are expediently prepared by reacting a compound of formula III above with a 2-halo-ethanol, preferably 2-chloro-ethanol, to yield a compound of the formula Bowman-NM R3 wherein R is as described above.

This reaction is preferably effected in polar solvent such as, for example. an alkanol, i.e., methanol, ethanol and the like, dimethylformamide or dimethyl sulfoxide. It is preferable to carry out this reaction in the presence of an acid binding agent, for example, in the presence of an alkali carbonate such as potassium carbonate and at a temperature between room temperature and the reflux temperature of the reaction medium.

The compound of formula IX thus obtained can subsequently be reacted with a halogenating agent such as thionyl chloride to yield the desired starting material of formula VIII in which L represents a halogen atom. This halo genation is preferably effected in the presence of an inert solvent, for example benzene or chloroform, at a temperature between room temperature and the reflux temperature of the reaction mixture.

The compound of formula IX above can alternatively be reacted with an alkylor arylsubstituted sulfonic acid halide, preferably the chloride, to give the desired starting material of formula VIII in which L represents an alkylor arylsubstituted sulfonyloxy group. This reaction is expediently effected in the presence of an acid binding agent, for example, pyridine or triethylamine, at a temperature between about C and room temperature.

C. In a further process aspect of the present invention, the desired compounds of formula I above can be prepared by dehydrating a compound of the formula Ti -N wherein R R R and X are as described above.

The dehydration of the compounds of formula X above in effected employing conventional techniques, as for example by treating said compound with a standard dehydrating agent. Suitable dehydrating agents for this purpose include acetic acid anhydride, acetyl chloride, thionyl chloride, p-toluenesulfonic acid, sulfuric acid, aluminum oxide, calcium chloride and the like. This dehydration reaction is expediently effected in an inert organic solvent such as chloroform, toluene, or glacial acetic acid and at a temperature between room temperature and the reflux temperature of the reaction mixture.

The starting materials of formula X can, for example, be prepared by reacting a compound of formula II above with an appropriately substituted 4-hydroxy-4- phenyl-piperidine. This reaction is preferably effected in a polar solvent such as an alkanol, i.e., methanol, ethanol and the like, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran and in the presence of an acid binding agent such as alkali carbonate, preferably potassium carbonate. The temperature range for this reaction is preferably between room temperature and the reflux temperature of the reaction medium.

D. In another process aspect of this invention, the desired compounds of formulal above can be prepared by treating a compound of the general formula wherein R R R and X are as described above with a mineral acid.

The treatment of the starting material of formula XI with a mineral acid is preferably carried out using concentrated hydrochloric acid. In so doing, the acid treat ment of the formula XI compound is effected at a temperature between about 0C and the reflux temperature of the reaction mixture, preferably at an elevated temperature, for a prolonged period, for example between 3 to 6 hours. It should be noted that any lower alkanoyl group present in the starting material of formula XI as the R substituent will be saponified under these reaction conditions.

The starting materials of formula XI above can, for example, be prepared by reacting a compound of formula II above with an appropriately substituted 6- methyl-6-phenyl-tetrahydro-l,3-oxazine. This reaction is preferably effected in a polar solvent such as an alkanol, i.e. methanol, ethanol and the like, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran and in the presence of an acid binding agent such as, for example, an alkali carbonate, preferably potassium carbonate. This reaction is expediently carried out at a temperature between room temperature and the reflux temperature of the reaction mixture.

E. In a further process aspect of this invention, the compounds of formula I above wherein R and R each signify hydrogen can be prepared by reducing a compound of the general formula are; .w

wherein R R and X are as described above and R, X-CH -CH N R signifies hydrogen, lower alkyl, lower alkanoyl,

' cycloalkyl or cycloalkyl-lower alkyl. The starting material of formula XIII is reduced by Q2 5 treatment of said compound with a complex metal XII hydride, preferably lithium aluminum hydride. This wherein R and X are as described above.

The reduction of the starting material of Formula XII is preferably carried out by treatment of said compound with hydrazine in the presence of a noble metal catalyst such as palladium on charcoal or platinum oxide. Alternatively, the reduction can also be carried out by treatment of the formula XII compound with sodium dithionite or with nascent hydrogen which can be provided, for example, by using a mineral acid such as hydrochloric acid and a metal which is capable of liberating hydrogen such as zinc or iron. This reduction is expediently conducted in the presence of a lower alkanol, preferably ethanol, or in a cyclic ether, prefer ably tetrahydrofuran. The reduction is preferably carried out at a temperature between room temperature and the reflux temperature of the reaction mixture.

The starting materials of formula XII can be prepared, for example, by condensing a 4-nitro-1-(2-haloethoxy or 2-haloethylthio)-benzene with a compound of formula III above. The conditions employed for the condensation of the appropriately substituted benzene compound with the formula III compound are essentially the same as those described in process aspect A above for the condensation of compounds of formulae II and III.

F. In another process aspect of the instant invention, a compound of the general formula wherein R and X are as described above; R signifies hydrogen, lower alkyl, lower alkanoyl, cycloalkyl or cycloalkyl-lower alkyl; R signifies hydrogen, lower alkyl, cycloalkyl or cycloalkyl-lower alkyl; or R and R together each represents an oxygen atom is reduced to yield a compound of the formula reduction is preferably effected in an organic solvent such as ether, tetrahydrofu ran, dioxane or diglyme, and at a temperature between about 0C and the reflux temperature of the reaction mixture. If, in the starting materials of formula XIII, R and R each signify an oxygen atom, the nitro group present in the starting material is first reduced following the procedures set forth in process aspect E above, and then the acid amide function is reduced as described above.

The starting materials of formula XIII can,.for example, be prepared by reacting a compound of the general formula XIV wherein R10, R and X are as described above with a compound of formula III above. The halogen leaving group in the compounds of formula XIV is preferably chlorine. This reaction is expediently effected in the presence of an inert organic solvent such as benzene or chloroform and in the presence of an acid-binding agent, preferably a tertiary organic base such as triethylamine or pyridine. The reaction is preferably carried out at a temperature between 0C. and the reflux temperature of the reaction mixture.

G. The compounds of formula I above wherein R signifies lower alkyl, lower alkanoyl, lower alkylsulfonyl, cycloalkyl or cycloalkyl-lower alkyl can be prepared following conventional techniques by introducing the desired R substitutent into the corresponding compound of the formula I wherein R signifies hydrogen, i.e., into a compound of the formula wherein R R and X are as described above.

The introduction of the desired R substitutent into the compound of formula Id above can be affected following conventional alkylating, alkanoylating or alkylsulfonylating techniques. Thus, for example, a lower alkyl, cycloalkyl or cycloalkyl-lower alkyl group can be introduced using standard alkylating procedures as by reacting the formula Id compound with an appropriate alkylating agent such as methyl iodide, cyclopropyl-bromide, dimethyl sulfate and the like. In a further example, the compound of formula Id can be treated with an appropriate acid halide or acid anhydride such as acetyl chloride, acetic anhydride, cyclopropane carboxylic acid chloride or methane sulfonic acid chloride to yield the correspondingly substituted compound of formula I. The treatment with an acid chloride is preferably effected in the presence of an acid-binding agent, for example, a tertiary organic base such as triethylamine or pyridine, and an inert organic solvent such as benzene, chloroform, tetrahydrofuran or dimethyl sulfoxide and at a temperature between room temperature and the reflux temperature of the reaction medium. The treatment with an acid anhydride is pref erably effected in a polar protonic solvent such as an alkanol, for example methanol, or in the presence of a dilute alkanecarboxylic acid, for example, dilute acetic acid. This reaction is expediently carried out at a temperature between about and about 50C., preferably at room temperature.

This process aspect represents a preferred procedure for the preparation of the compounds of formula I above wherein R signifies a lower alkyl-sulfonyl group. It is also the preferred procedure for introducing a lower alkylsulfonyl group, when desired, into the starting materials of formulae II, VII, X and XI above wherein R signifies hydrogen.

The compounds of formula I above wherein R signifies a lower alkanoyl group can be saponified following conventional techniques, as for example, by treating said compound with dilute aqueous caustic alkali or with aqueous acid. It is advantageous to use about percent hydrochloric acid at an elevated temperature, especially at the reflux temperature of the reaction mixture.

The compounds of formula I above are basic and thus form acid addition salts with both pharmaceutically acceptable organic or inorganic acids, for example, with hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid, with other mineral acids such as sulfuric acid, phosphoric acid and nitric acid, as well as with organic acids such as tartaric acid, citric acid, oxalic acid, camphorsulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, ascorbic acid, maleic acid, mandelic acid and the like. Preferred salts are the hydrohalides, especially the hydrochlorides. The acid addition salts are preferably manufactured in a suitable solvent such as ethanol or acetonitrile by treatment of the free base with the corresponding non-aqueous acid.

The compounds of formula I above are, in part, crystalline substances which are relatively readily soluble in dimethyl sulphoxide, dimethylformamide, in chlorinated hydrocarbons such as, for example, chloroform or methylene chloride and in alkanols such as methanol or ethanol, but which are relatively insoluble in water.

The acid addition salts of the compounds of formula I are crystalline substances. They are readily soluble in dimethyl sulphoxide, dimethylformamide, in alkanols such as methanol or ethanol and, usually, also in water.

They are relatively insoluble in benzene, petroleum ether and in chlorinated hydrocarbons such as, for example, chloroform or methylene chloride.

As indicated above, the compounds of formula I above exhibit psychosedative activity. The psychosedative activity of the tetrahydropyridine derivatives of formula I is demonstrated in warm blooded animals using the standard open field test with rats [Psychop/zarmacologia I, 389392 (1960)]. The dosage which caused a 50 percent decrease (in comparison to the untreated controls) in the number of diameter crossings is expressed as the ED The results of the test for representative compounds of formula I are shown in the following Table:

The tetrahydropyridine derivatives provided by this invention can be used as medicaments; for example, in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier. This carrier can be an organic or inorganic inert carrier material which is suitable for enteral or parenteral application such as, for example, gelatin, gum arabic, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. The pharmaceutical preparations are preferably made up in solid form (e.g., as tablets, dragees, suppositories or capsules). They can also contain yet other therapeutically valuable substances.

Expedient pharmaceutical dosage forms contain about 5l00 mg. of a compound of formula I. Expedient oral dosage ranges lie at about 0.l mg/kg/day to about 10 mg/kg/day. However, the stated ranges can be extended upwards or downwards depending on the individual requirement of the patient or the directions given by the specialist.

The starting materials of formulae X, XI, XII, and XIII are novel and as such form a part of the present invention. The following examples further illustrate the scope of the noted invention. Unless otherwise indicated, the temperature stated are in degrees centigrade.

EXAMPLE I 21.4 g. of 4-(p-fluorophenyl)-l,2,3,6-tetrahydropyridine hydrochloride, 25.8 g; of 4-(2-bromoethoxy)acetanilide, 30 g. of potassium carbonate and a few crystals of potassium iodide are heated under reflux conditions in 200 ml. of ethanol and 20 ml. of water for 24 hours. While still hot, the mixture is decanted from the aqueous phase, ml. of water are added and the mixture is allowed to cool, with crude 4-{2-[4-(pfluorophenyl )-3 ,6-dihydro-1 (2H )-pyridyl ethoxy}acetanilide crystallizing out of solution. This is dissolved in a mixture of ml. of methanol and 50 ml. of acetic acid ethyl ester and converted by addition of alcoholic hydrochloric acid, until the mixture becomes ester) from 4'-(2-bromoethoxy)isobutyranilide and.

4-( p-fluorophenyl l ,2,3,6-tetrahydropyridine;

d. 4-{2-[4-(p-chlorophenyl)-3.6-dihydro-12H)pyridyl]ethoxy}acetanilide hydrochloride, m.p. 228229C. (from methanol-acetic acid ethyl ester) from 4-(2-bromoethoxy)acetanilide and 4-(p-chlorophenyl )-l ,2,3 ,6-tetrahydropyridine;

e. 4'- {2-[4-(p-methoxyphenyl )-3 ,6-dihydro- 1 (2H pyridyl]ethoxy}acetanilide, m.p. l63l64C. (from methanol) from 4'-(2-bromoethoxy)acetanilide and 4-(p-methoxyphenyl)- 1 ,2.3,6-tetrahydropyridine.

The 4-(2-bromoethoxy)propionanilide employed as a starting material can be manufactured as follows:

82.5 g. of p-propionamidophenol are introduced into a solution of 20 g. of sodium hydroxide in 20 ml. of water and 400 ml. of ethanol and, with strong stirring, treated with 470g. of 1,2-dibromoethane. The mixture is heated under reflux conditions for 3 hours and the dibromoethane is driven off with the aid of steam. The crude 4'-(2-bromoethoxy)propionanilide which precipitates is washed with water and recrystallized from ethanol with the addition of water. The compound melts at 151C.

The 4'-(2-bromoethoxy)isobutyranilide employed as starting material can be manufactured in a manner analogous to that described above, mp 143C. (from ethanol).

EXAMPLE 2 1.8 G. of 4-[(2-chloroethyl)thio]acetanilide, 2.7 g. of 4-(p-fluorophenyl)-l,2,3,6-tetrahydropyridine, 4.5 g. of potassium carbonate and a few crystals of potassium iodide are heated under reflux conditions in 50 ml. of ethanol and 5 ml. of water for 16 hours. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform and washed with water. From the organic phase there is obtained crude 4'-{[2- [4-(p-fluorophenyl)-3,6-dihydr0-l (2H )-Py idyl]- ethyl]thio}acetanilide which melts at l50152C. after recrystallization from acetic acid ethyl ester.

The 4'-[( 2-chloroethyl )thio]-acetanilide employed as starting material can be manufactured as follows:

A solution of 17.5 g. of 4'-[(2-hydroxyethyl)thio]- acetanilide in 500 ml. of absolute benzene is treated dropwise with stirring with 17.5 g. of thionyl chloride and heated under reflux conditions for 1 hour. The crude 4-[(2-chloroethyl)thio]-acetanilide remaining behind after evaporation of the solvent under reduced pressure melts at 153155C. after repeated crystallization from acetic acid ethyl ester. A further crystallization can be obtained from the mother liquor by adsorption on silica gel and elution with methylene chloride.

EXAMPLE 3 7.8 G. of 4-{2- [4-(pfluorophenyl)-3 ,6-dihydro- 1(2H)-pyridyl] -ethoxy}acetanilide and 40 ml. of about 20% hydrochloric acid are heated under reflux conditions for 1 hour. The crude p-{Z- [4-(p-fluorophenyl)- 3 ,6-dihydr0-l (2H)-pyridyl] ethoxy} aniline dihydrochloride hydrate which precipitates on cooling melts at 183C. after recrystallization from ethanolacetic ester-diethyl ether.

EXAMPLE 4 0.8 G. of p{2-[4-(p-fluorophenyl)-3,6-dihydrol(2H)pyridyl]ethoxy}aniline are dissolved in 10 ml. of 3-N acetic acid and treated with 0.5 g. of acetic acid anhydride. The solution is stored at room temperature for 12 hours and subsequently evaporated under reduced pressure. The residue is taken up in chloroform, this extract washed with l-N caustic soda and evaporated. The residual crude 4-{2-[4-(p-fluorophenyl)- 3,6-dihydro- 1(21-1 )-pyridyl ]ethoxy} acetanilide melts at 139C. after recrystallization from acetic acid ethyl ester.

EXAMPLE 5 A solution of 4.5 g. of p-{2-[4-(p-fluorophenyl)-3,6- dihydro-l(2H)-pyridyl]ethoxy}aniline in 15 ml. of chloroform is treated with 2 g. of triethylamine. A solution of 1.7 g. of methanesulfonic acid chloride in 10 ml. of chloroform is added thereto with stirring and cooling at a temperature range of 010C. The reaction mixture is allowed to stand at room temperature for 20 hours. It is washed with water and the solvent is evaporated. The residual crude 4-{2-[4-(p-fluorophenyl)-3,6-dihydro- 1 (2H )-pyridyl]ethoxy}- methanesulfonanilide melts at l37l39C. after recrystallization from methanol.

EXAMPLE 6 0.1 G. of 4 {2-[4-(p-fluorophenyl)-4-hydroxypiperidino]ethoxy}acetanilide are dissolved in 30 ml. of chloroform with slight heating and 0.2 g. of thionyl chloride are added. The mixture is heated under reflux conditions for 4 hours. The crude 4'- {2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]-ethoxy}acetanilide hydrochloride remaining after evaporation of the solvent melts at 213215C. (dec.) after recrystallization from methanol-diethyl ether.

The 4- {2-[4-(p-fluorophenyl )-4-hydroxypiperidino]ethoxy}acetanilide employed as starting material can be manufactured as follows:

1.3 G. of 4-(p-fluorophenyl)-4-hydroxypiperidine, 1.85 g. of 4-(2-bromoethoxy)-acetanilide, l g. of potassium carbonate and a few crystals of potassium iodide are heated under reflux conditions in 20 ml. of isopropanol for 24 hours. The residue remaining after evaporation of the solvent is taken up in chloroform and washed with water. The crude 4- {2-[4-(p-fluorophenyl)-4-hydroxypiperidino]-ethoxy}acetanilide ob tainable from the organic phase melts at l74l75C. after recrystallization twice from isopropanol.

13 yl-2H-1,3-oxazin-3(4H)-yl]ethoxy}acetanilide hydrochloride and 2 ml. of cone. hydrochloric acid are heated on the steam bath for 4 hours. The excess hydrochloric acid is evaporated under reduced pressure and the residue brought to crystallization with ethanolacetic acid ethyl ester. The p-{2-[4-(p-fluorophenyl)- 3,6-dihydro-1(2H)-pyridyl]ethoxy}aniline dihydrochloride hydrateobtained melts at 180183C. after recrystallization from ethanol-acetic acid ethyl ester.

The 4 {2-[6-(p-fluorophenyl)-dihydro 6-methyl- 2H-1,3-oxazin-3(4H)-yl]-ethoxy}-acetanilide employed as starting material can be manufactured as follows: I

5.2 G. of 4'-(2-bromoethoxy)acetanilide, 4 g. of 6- methy1-6-(p-fluorophenyl)-tetrahydro- 1 ,3-oxazine, 5 g. of potassium carbonate and a few crystals of potassium iodide are heated under reflux conditions in 50 ml. of ethanol for 16 hours. After evaporation of the solvent under reduced pressure, the residue is dissolved in chloroform and washed with water. The crude product obtained from the organic phase is adsorbed on silica gel and purified by elution with methylene chlorideether 1:1 There is obtained an oil which isconverted. into the hydrochloride as previously described. The pure 4- {2-[6-(p-fluorophenyl )-dihydro-6-methyl-2H- l,3-oxazin-3(4H )-yl]ethoxy} acetanilide melts 180C. (dec.) after recrystallization from acetic acid ethyl ester.

EXAMPLE 8 A solution of 0.3 g. of 1-[(p-aminophenoxy)acetyl]- 4-(p-fluorophenyl)-l,2,3,6-tetrahydropyridine in 5 ml. of absolute tetrahydrofuran is added dropwise at room temperature with stirring and nitrogen gassing to a suspension of 0.3 g. of lithium aluminum hydride in 10 ml. of absolute tetrahydrofuran. The stirring is continued at room temperature for 16 hours and water is cautiously added, initially dropwise. After filtration, the mixture is extracted with chloroform. The oily residue is purified by column chromatography on silica gel with diethyl ether-acetic acid ethyl ester 1:1) as eluting agent and converted into the hydrochloride as previously described. The p- {2-[4-(p-fluorophenyl)-3,6- dihydro-l (2H )-pyridyl -ethoxy} aniline dihydrochloride hydrate melts at 180-183C. after crystallization with ethanol-acetic acid ethyl ester-ether.

The 1-[ p-aminophenoxy )-acetyl]-4-( p-fluorophenyl)-1,2,3,6-tetrahydropyridine employed as starting material can be manufactured as follows:

A solution of 4.3 g. of p-nitrophenoxyacetic acid chloride in 10 ml. of absolute benzene is added dropwise with stirring and cooling to a solution of 3.6 g. of p-fluorophenyl-l,2,3,6-tetrahydropyridine and 5 g. of triethylamine in 20 ml. of absolute benzene and the reaction mixture is heated under reflux conditions for 1 hour. After cooling, the triethylamine hydrochloride thereby precipitated is extracted with water and the organic phase is washed with 1N hydrochloric acid and water. The crude 4-( p-fluorophenyl)-l ,2,3,6-tetrahydrol-[ p-nitrophenoxy )-acetyl]pyridine obtained after evaporation of the solvent melts at l34136C. after recrystallization from isopropanol.

2.3 g. of this compound and 2.5 g. of hydrazine hydrate are dissolved in 50 ml. of absolute tetrahydrofuran. 0.2 G. of platinum dioxide are added portionwise commencing the strong evolution of nitrogen. After cessation of the evolution of gas, the mixture is heated under reflux conditions for hours and subsequently filtered. After evaporation of the solvent. the residue is purified by column chromatography on silica gel with methylene chloride as eluting agent. The 1-.[(p-aminophenoxy)-acetyl]-4-( p-fluorophenyl 1 ,2,3,6-tetrahydropyridine obtained from the eluate melts at l20-122C. after recrystallization from benzene.

EXAMPLE 9 and eluted with methylene chloride-ether (1:1). The

4- {2-[4-(p-fluorophenyl )-3,6-dihydro- 1 (2H)- pyridyl]-ethoxy}-acetanilide obtained from the eluate melts at 139C. after recrystallization from acetic acid ethyl ester.

The 1-(2-chloroethyl)-4-(p-fluorophenyl)-1,2,31,6-

' tetrahydropyridine employed as starting material can be manufactured as follows:

1.77 g. of 4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine, 0.8 g. of ethylene chlorohydrin, 1.2 g. of sodium carbonate and a few crystals of sodium iodide are heated under reflux conditions in 10 ml. of ethanol for 24 hours and filtered hot and the filtrate is evaporated to dryness. The residual oil is purified by column chromatography on silica gel with acetic acid ethyl esterethanol (1:1 as eluting agent. The 1-( 2-hydroxyethyl)- 4-(p-fluorophenyl l ,2,3,6-tetrahydropyridine obtained from the eluate melts at 9698C. after recrystallization from cyclohexane.

0.5 g. of l-(2-hydroxyethyl)-4-(p-fluorophenyl)- 1,2,3,6-tetrahydropyridine are dissolved in 10 ml. of absolute benzene and 0.4 g. of thionyl chloride are added with stirring and cooling with ice. The mixture is heated under reflux conditions for 30 minutes and the solvent is evaporated. The l-(2-chloroethyl)-4-(pfluorophenyl 1 ,2,3 ,6-tetrahydropyridine hydrochloride obtained melts at 226C. after recrystallization from ethanol.

EXAMPLE 10 0.2 g. of powdered iron is added to a solution of 0.34 g. of 4-(p-fluorophenyl)-1.2,3,6-tetrahydro-l-[2-(pnitrophenoxy) ethyl]pyridine in a mixture of 2 ml. of 1N hydrochloric acid. 10 ml. of ethanol and 10 ml. of water. The mixture is refluxed for 4 hrs., cooled and made alkaline by addition of 1N sodium hydroxide. After addition of 20 ml. of chloroform and celite, the mixture is filtered. The organic phase is separated. dried and evaporated. The oily residue obtained is dissolved in ethyl acetate and converted to the hydrochloride by addition of ethanolic hydrogen chloride. The 1-[2-(p-aminophenoxy)ethyl]-4-(p-fluorophenyl)- 1,2,3,6-tetrahydropyridine dihydrochloride obtained in this way has m.p. 180l 8 1 after recrystallization from ethanol/ethylacetate/ether.

The starting material may be prepared as follows:

A mixture of 2.15 g. of 4-(p-fluorophenyl)-1,2.3,6- tetrahydropyridine hydrochloride, 2.5 g. of p-(2- bromoethoxy)nitrobenzene, 2.8 g. of potassium carbonate, 20 ml. of ethanol and 2 ml. of wate f' 1% refluxed for 3 days. After filtration the crude prodHGiEfystallizes from the hot reaction mixture. It is plilified by 15 chromatography on silica gel using methylene chloride for elution. The 4-(p-fluorophenyl)-l ,2,3,6-tetrahydrol-[Z-(p-nitrophenoxy)ethyl]pyridine obtained melts at l04-l07 after recrystallization from ethanol.

EXAMPLE 1 1 Manufacture of capsules of the following composition:

4-{2-[4-(p-fluorophenyl )-4.6-dihydrol 2H )-pyridyl lethoxy} acetanilide hydrochloride Mannitol Talcum mg. 110 mg.

5 mg. 125 mg.

The active substance is homogeneously mixed with the talcum and mannitol, passed through a No. 5 sieve (mesh width about 0.23 mm) and again thoroughly mixed. The mixture obtained is filled into No. 4 gelatin capsules.

EXAMPLE 12 Manufacture of dragees of the following composition:

hydrochloride 25 mg. Munnitol I00 mg. Corn starch 20 mg. Talcum 5 mg. mg.

wherein R signifies fluorine, chlorine or lower alkoxy and X signifies an oxygen atom or a sulfur atom. 

1. A COMPOUND OF THE FORMULA 